EP1748805A1 - Resorbierbare biokompatible materialien - Google Patents

Resorbierbare biokompatible materialien

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Publication number
EP1748805A1
EP1748805A1 EP05746512A EP05746512A EP1748805A1 EP 1748805 A1 EP1748805 A1 EP 1748805A1 EP 05746512 A EP05746512 A EP 05746512A EP 05746512 A EP05746512 A EP 05746512A EP 1748805 A1 EP1748805 A1 EP 1748805A1
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EP
European Patent Office
Prior art keywords
group
copolymer
coating
hydrophobic
monomer unit
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP05746512A
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English (en)
French (fr)
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EP1748805B1 (de
Inventor
Ajay Kumar Luthra
Shivpal Singh Sandhu
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BioInteractions Ltd
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BioInteractions Ltd
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/044—Proteins; Polypeptides; Degradation products thereof
    • A61L29/048—Other specific proteins or polypeptides not covered by A61L29/045 - A61L29/047
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings

Definitions

  • the field of the invention is generally related to bioabsorbable biocompatible coatings for delivery of therapeutic agents, and may include coatings made with polypeptides modified with hydrophobic side chains.
  • vascular stents may release therapeutic agents after deployment in the vasculature.
  • the therapeutic agent may be deployed in a carrier material, also referred to as a vehicle, that is not absorbable and/or degradable.
  • Biocompatible carrier materials are described herein for enhanced delivery of therapeutic agents.
  • One embodiment is a degradable material that includes at least one amino acid that has been modified to include a hydrophobic side chain.
  • the number and type of amino acids and hydrophobic side chains may be altered to adjust the properties of the material.
  • hydrophilic groups may also be introduced as a further means to adjust the material's property.
  • Some embodiments are directed to a coating and a method of making a coating, e.g., on a surface of a medical device, by forming (an optionally biodegradable) layer on at least a portion of the surface of the medical device, the layer comprising a copolymer and a therapeutic agent releasable into a patient after implantation of the device into the patient, wherein the copolymer comprises a first monomer unit and a second monomer unit, with the first monomer unit comprising an amino acid and the second monomer unit comprising an amino acid derivatized to have a hydrophobic hydrocarbon side chain that has a molecular weight from about 14 to about 5000.
  • inventions are directed to a coating and a method of delivering a therapeutic agent with a medical device, the method comprising: applying a layer comprising the therapeutic agent and water soluble polyamino acids to at least a portion of a surface of the medical device and crosslinking the polyamino acids to each other to stabilize the layer, wherein the therapeutic agent is releasable when the medical device is implanted in a patient.
  • Figure 1 depicts the cumulative release of a therapeutic agent from a layer of derivatized polyamino acid
  • Figure 2 depicts the embodiment of Figure 1, with the release of the therapeutic agent being depicted on a per day basis
  • Figure 3 depicts the adjustment of a layer's properties for control release of a therapeutic agent, with the structures of three different polyamino acids being adjusted to have hydrophobic side chains of different lengths
  • Figure 4 depicts the embodiment of Figure 3, with the release of the therapeutic agent being depicted on a per day basis.
  • Materials with amino acids with side chains modified to have hydrophobic moieties may be used as coatings on medical devices to deliver drugs, and these materials can be referred to as carrier materials.
  • polyamino acids are decorated with hydrophobic groups to change the solubility of the polyamino acids in organic solvents.
  • the degree of a derivatized polyamino acid's hydrophobicity may be controlled to influence compatibility with solvents and the rate of release of drugs associated with the polyamino acid.
  • hydrophilic groups may be introduced into the polyamino acids to further control solubility and release profiles.
  • a polyamino acid may be decorated with hydrophobic groups as needed to solubilize the polyamino acid in a solvent that is desired for a particular therapeutic agent. Then the polyaminoacid and the agent may both be solubilized in the same solvent to form a composition that may be deposited as a layer on a surface of a medical device.
  • Medical devices such as stents, catheters, guidewires, vascular grafts, wound closure devices and the like are continually being used in many clinical procedures. The performance of these devices can be enhanced by delivery of therapeutic, diagnostic, or other agents to site specific regions within the patient and it is desirable to provide the delivery from a degradable and biocompatible vehicle.
  • the carrier materials may be biocompatible, and/or degradable, and/or absorbable, and/or clearable.
  • Degradable refers to a process of breaking down into smaller pieces.
  • Hydrolytic degradation is a process of degradation that is facilitated by exposure to water.
  • Bioactive degradation is a process of degradation that is mediated by a cell or cellular product, and includes the action of proteases, enzymes, and free radical attack by macrophages.
  • Absorbable is a term used herein to indicate materials that break down into components that can be used, recycled, or completely destroyed by the body's biological processes.
  • amino acids, polypeptides, and fatty acids are believed to be absorbed after their introduction into the body, and may be directly integrated into metabolic processes or may be destroyed, e.g., in a lysosome.
  • Clearable materials are materials that are cleared from the body, for example, via urine or sweat.
  • embodiments are described herein that include polypeptide derivatives that are biocompatible and bioabsorbable. Their preparation, characterization and method of use are also described.
  • Amino acid is a term used herein to refer not only to a free amino acid, but also to amino acids that have been reacted with each other, or with linking groups. When reacted to form a larger molecule, the amine terminal group and the carboxylic acid terminal group of the amino acid can be recognized within the larger structure such that the presence of the amino acid can be identified.
  • An amino acid may be a natural or synthetic amino acid. Natural refers to an amino acid found in nature, while synthetic refers to an amino acid not found in nature. Amino acids include D or L forms, and those amino acids having a derivatized backbone.
  • Certain embodiments are directed to derivatized amino acids, meaning a chemical structure that can be achieved by adding or substituting groups the an amino acid's N-terminus, C-terminus, side chain, or all three.
  • a molecule is referred to as being decorated, meaning that a group has been added to a molecule, usually by replacement of at least one other group.
  • An amino acid may be a moiety derived from a natural amino acid, e.g., alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • a natural amino acid e.g., alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • R is -(CH 3 ) (referred to as R 3 ).
  • polylysine is a homo-amino acid sequence, meaning it has all the same type of amino acids.
  • the formulae for R for natural amino acids are well known.
  • the C that is bonded to the R is referred to as the alpha carbon.
  • Polyamino acids may have a formula of H 2 N- ⁇ CH[R]-L ⁇ profession - COOH (Formula 3) wherein R is a side chain group and L is a linking group between the alpha carbons.
  • L is a linking group between the alpha carbons.
  • the structure of L will depend on the groups on the alpha carbon of an amino acid that are reacted to form the linkages between the alpha carbons.
  • Other linking groups are applicable for polypeptides having alternative backbones.
  • a polyaminoacid may be a gamma polyaminoacid formed through amino acid gamma carbons, e.g., wherein the N-terminus of an amino acid is reacted with a carboxylic acid of a side chain of another amino acid to form a bond.
  • a gamma polyamino acid may have some or all of the amino acids therein linked via the gamma carbons.
  • N-terminus and C-terminus of a polypeptide may be modified using chemistries known to persons of ordinary skill in these arts so that a polypeptide may be represented as Yn- ⁇ CH[R]-L ⁇ n - Yc, with Yn and Yc being independently chosen to be H, a halogen, a hydroxyl group, a thiol group, a carboxyl group, an amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkynyl group.
  • Yn and/or Yc may be chosen to be X*, as set forth with reference to Formula 4, below.
  • An embodiment is a material that comprises a chemical having a formula of A-Z-T (Formula 4), wherein A is a natural or synthetic amino acid derivatized with Z and T; Z is a bond, or a linking group that links the indicated groups, A and T, by covalent bond(s) and may include an aliphatic group and at least one heteroatom such as P, O, S, and N, the aliphatic group may be, e.g., an alkane, alkene, alkyne, or combinations thereof, the linking group Z may include, e.g., between about 1 and about 100 atoms; and T has a formula of H or -(CH ) n -X* group, wherein X* is a H, a halogen, a hydroxyl group, a thiol group, a carboxyl group, an amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkynyl group, and -(
  • T comprises a hydrophobic aliphatic group with n being between about 2 and about 100, and may include an aliphatic group and at least one heteroatom such as P, O, S, and N.
  • the aliphatic group may be, e.g., an alkane, alkene, alkyne, or combinations thereof.
  • the aliphatic chain may, furthermore, have at least one, or between about 1 and about 50 hydrophobic aliphatic groups; persons of ordinary skill in these arts will immediately appreciate that every value and range within the explicitly articulated range of 1-50 is contemplated.
  • Z and T may therefore be chosen to be any side chain of an amino acid.
  • Z may be chosen to be a bond and T may be chosen to be H so that a CH group is formed on a backbone.
  • An embodiment is a material that comprises a chemical having a formula of
  • n is an integer between about 1 and about 500,000;
  • Z n are independently chosen to be a bond, or a linking group that links the indicated C to T, by covalent bond(s) and may include an aliphatic group and at least one heteroatom such as P, O, S, and N, the aliphatic group may be, e.g., an alkane, alkene, alkyne, or combinations thereof, the linking group Z may include, e.g., between about 1 and about 100 atoms; and Yc and Yn are each independently chosen to be H, a halogen, a hydroxyl group, a thiol group, a carboxyl group, an amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group a siloxane or a functional group.
  • Yn and/or X* may be defined as X*, as set forth with reference to Formula 4, above.
  • T ls T2, and T3, are each chosen independently, as may be Z ls Z , and Z 3 .
  • Tn, or Tn and Zn together are each chosen independently, as may be Z ls Z , and Z 3 .
  • Tn having a formula of H or -(CH 2 ) n -X* group comprises a hydrophobic aliphatic group with n being between about 1 and about 100, and may include an aliphatic group and at least one heteroatom such as P, O, S, and N.
  • the aliphatic group may be, e.g., an alkane, alkene, alkyne, or combinations thereof. Persons of ordinary skill in these arts will immediately appreciate that every value and range within the explicitly articulated range is contemplated, not only for the range immediately preceding this statement, but for other ranges set forth herein.
  • Tn comprises between about 4 and about 100 (CH 2 ) with between about 1 and about 50 of the (CH ) being substituted with at least group having at least one heteroatom such as P, O, S, and N.
  • a compound of Formulas 5-8, Tn comprises a functional group, FG, for forming a covalent bond with another functional group, e.g.,: as shown in Formula 7:
  • FGn denotes an optional functional group FGi. . . FGn.
  • examples of FG are: polymerizable groups (e,.g., vinylics groups, groups polymerizable by free radical, addition, condensation polymerization) a carboxyl, amino, hydroxyl or acid chloride, anhydride, isocyanate, thiocyanate, azides, aldehyde, ketone, thiol, allyl, acrylate, methacrylate, epoxide, aziridines, acetals, ketals, alkynes, acyl halides, alky halides, hydroxy aldehydes and ketones, allenes, amides, bisamides, and esters, amino carbonyl compounds, mercaptans, amino mercaptans, anhydrides, azines, azo compounds, azoxy compounds, boranes, carbamates, carbodimides, carbonates, diazo compounds, isothionates, hydrox
  • the Formulas 5-8 may thus be used to describe compounds that are polymers, block polymers, or random polymers.
  • a polypeptide backbone can consist of lysine where Ri is-(CH 2 ) -NH 2 and as such the amine is able to chemically react with an acid chloride, an acid anhydride, isocyanate, and with other functional groups.
  • a polypeptide backbone as found in nature has an amide linking group, as shown in the embodiment of Formula 8:
  • Tn is defined as set forth in reference to Formulas 5 and 6; alternatively Tn may be chosen only to comprise H or a linear or branched aliphatic group, e.g., -Cso, or C 4 - C 25 . Alternatively, substitution of heteroatoms into the aliphatic may also be employed, e.g., O, S, P, and N.
  • Zn is defined as set forth in reference to Formulas 5 and 6; alternatively Zn may be chosen as a bond or a linker that comprises between 2 and 5, 10, 15, or 20 atoms, and forms a covalent bond between Tn and C.
  • Zn may be chosen to be a bond or an amino acid side chain that is derivatized to form a bond between the side chain and Tn.
  • Polypeptides, polypeptide backbones, or molecules comprising polypeptides may be homoaminoacid or heteroaminoacid sequences.
  • a polypeptide may be a block copolymer, an alternating copolymer or a random polymer.
  • each block can have a set of the same amino acid types, e.g., KKKAAA, KKKAAAKKK, or KKKKKAAAKKAAAKKKKAAAA, wherein K and A are lysine and alanine, respectively.
  • the polymer can have a specific ordered structure, such as KAKAKAKAKAK, KKAKKAKKAKKAKKA, or KKIAAKKAAKKAAKKAA.
  • the block copolymers and alternating copolymer can have more than two types of amino acids as desired.
  • a polypeptide may be random, e.g., AKRCKKRACKRAAK, wherein A, K, C, and R are amino acids.
  • a backbone may comprise linking groups between amino acids, e.g., AKR-Z-AKR-Z-KKA-Z-C-Z-AA- wherein A, K, R, and C are amino acids and Z is a linking group, e.g., as defined herein with reference to Formulas 5 and 6.
  • the side chains of the amino acids maybe protected, unprotected, or derivatized, e.g., with aliphatic chains, e.g., C 2 to C 50 .
  • An embodiment is a polypeptide having a formula of:
  • Formula 9 wherein p l5 p 2 , . . . p admirably are units in a polypeptide sequence, and may be an amino acid with/without a derivitized side chain.
  • Yn, Tn, Zn and Yc may be defined as defined for other embodiments herein, e.g., Formulas 5-8.
  • the embodiment of Formula 9 may have a backbone that is a heteroaminoacid, a homoamino acid, and may have a block or random sequence.
  • side chains of amino acids in polypeptides may be derivatized with hydrocarbon chains, for example, saturated or mono-unsaturated or poly- unsaturated.
  • Such long chain hydrocarbons are, but not limited to, lauric acid, myristic acid, palmitic acid, stearic acid, oleic, acid, erucic acid, linoleic acid, (alpha)-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, 1-eicosanol, undecylamine, dodecylamine, dodecyl isocyanate, dodecenyl succinic anhydride, dodecanol, dodecanal, dodecanthiol, dodecanolactone, 2-dodecenedioic acid, cis-5- dodecenoic acid, cis-7-dodecen-l-ol, hexadecylamine, cis-9-hexadecenal, cis-11- hexadecen-1-ol, hexadeceny
  • Tn may be selected as a hydrocarbon chain, e.g., from C ⁇ to C 0 .
  • polypeptides may be between, e.g., about 4 and about 100,000 or between about 6 and about 10,000 amino acids in length, or with a molecular weight of amino acids between about 1000 - 4 million.
  • the term polypeptide is used herein to include embodiments that comprise a natural or synthetic amino acid that has been decorated with an alternate chemical moiety. Preparation of polypeptides and derivatized polypeptides can be performed by persons of ordinary skill in these arts after reading this disclosure. Polypeptide chemistry references incorporated by reference herein include, e.g., M.
  • Bodanszky "Peptide Chemistry", Springer- Verlag, 1988; Norbert Sewald, Peptides: Chemistry and Biology, Wiley, John & Sons, Incorporated, August 2002; Gregory A. Grant, Synthetic Peptides: A User's Guide, Oxford University Press, March 2002; Incorporated herein by reference are sources that provide additional details for reaction schemes for derivatizing peptides: T. W. Greene, Protective Groups in Organic Synthesis, 3rd Edition; Wiley: New York, 1999; R. C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, New York, 1989; B. M. Trost, I. Fleming (eds. -in-chief), Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry: Cumulative Indexes, Volume 9.
  • Substitution and substituents are liberally allowed on chemical groups, and on the atoms that occupy a position in a Formula depicted herein, for various physical effects on the properties of the compounds, such as mobility, sensitivity, solubility, compatibility, stability, and the like, as would be known to a person of ordinary skill in these arts after reading this disclosure.
  • chemical substituents there are certain practices common to the art that are reflected in the use of language.
  • group indicates that the generically recited chemical entity (e.g., alkyl group, alkenyl group, aromatic group, epoxy group, arylamine group, aromatic heterocyclic group, aryl group, alicyclic group, aliphatic group, heterocyclic non-aromatic group etc.) may have any substituent thereon which is consistent with the bond structure of that group.
  • chemical entity e.g., alkyl group, alkenyl group, aromatic group, epoxy group, arylamine group, aromatic heterocyclic group, aryl group, alicyclic group, aliphatic group, heterocyclic non-aromatic group etc.
  • alkyl group' that term would not only include unsubstituted linear, branched and cyclic alkyls, such as methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, dodecyl and the like, but also substituents having heteroatom such as 3-ethoxylpropyl, 4-(N-ethylamino)butyl, 3-hydroxypentyl, 2-thiolhexyl, 1,2,3-tribromoopropyl, and the like.
  • no substitution would be included within the term that would alter the fundamental bond structure of the underlying group.
  • substitution such as 1-aminophenyl, 2,4-dihydroxyphenyl, 1,3,5- trithiophenyl, 1,3,5-trimethoxyphenyl and the like would be acceptable within the terminology, while substitution of 1,1,2,2,3,3-hexamethylphenyl would not be acceptable as that substitution would require the ring bond structure of the phenyl group to be altered to a non-aromatic form because of the substitution.
  • alkyl refers to a saturated straight, branched, or cyclic hydrocarbon, and specifically includes, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • the alkyl group can be optionally substituted with any appropriate group, including but not limited to one or more groups selected from halo, hydroxyl, amino, alkylamino, arylarmino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art.
  • alkenyl unless otherwise specified, is a straight, branched, or cyclic (in the case of C5 -6 ) hydrocarbon with at least one carbon-carbon double bond, and may be substituted as described above.
  • alkynyl is a hydrocarbon, straight or branched, with at least one triple one carbon-carbon bond, and may be substituted as described above. In some embodiments, it is useful to limit the size of these substituents to, e.g., less than about 150, less than about 100, less than about 50, or less than about 20 atoms.
  • Other suitable substituent groups include these and other N-containing compounds e.g, amines, amides, amidium ions, amine imides, amine oxides, aminium ions, aminonitrenes, nitrenes, aminoxides, nitriles, and nitrile imides.
  • substituent groups include these and other S-containing compounds, e.g., sulfonic acid, sulfate, sulfonates, sulfamic acids, sulfanes, sulfatides, sulfenamides, sulfenes, sulfenic acids, sulfenium ions, sulfenyl groups, sulfenylium ions, sulfenyl nitrenes, sulfenyl radicals, sulfides, sulfilimines, sulfimides, sulfimines, sulfinamides, sulfinamidines, sulfines, sulfinic acids, sulfinic anhydrides, sulfinimines, sulfinylamines, sulfolipids, sulfenamides, sulfonamidines, sulfonediimines, s
  • substituent groups include these and other P-containing compounds, e.g., phosphanes, phosphanylidenes, phosphatidic acids, phosphazenes, phosphine oxides, phosphines, phosphinic acids, phosphinidenes, phosphinous acids, phosphoglycerides, phospholipids, phosphonic acids, phosphonifriles, phosphonium compounds, phosphonium ylides, phosphono, phosphonous acids, phosphoramides, and phosphoranes.
  • P-containing compounds e.g., phosphanes, phosphanylidenes, phosphatidic acids, phosphazenes, phosphine oxides, phosphines, phosphinic acids, phosphinidenes, phosphinous acids, phosphoglycerides, phospholipids, phosphonic acids, phosphonifriles, phosphonium compounds,
  • Carbon is useful for making substituents and the number of carbons in a heteroatomic structure may be, e.g., between 1 and n-1 when between 2 and n atoms are used to form a substituent with, e.g., O, P, S, or N. In some embodiments, it is useful to limit the size of these substituents to, e.g., less than about 150, less than about 100, less than about 50, or less than about 20 atoms.
  • the formulas set forth herein describe a variety of groups. All of these various groups may be optionally derivitized with substituent groups, as already described.
  • Suitable substituent groups that may be present on such a "substituted" group include e.g., halogens such as fluoro, chloro, bromo and iodo; cyano; H, hydroxyl group; ester group; ether group; a carbamate, an oxo acid group, an oxocarbon group, an oxo carboxylic acid group, an oxo group, a ketone group; nitro; azido; sulfhydryl; alkanoyl e.g., C 1-6 alkanoyl group such as acetyl and the like; carboxamido; alkyl groups, alkenyl and alkynyl groups including groups having one or more unsaturated linkages; alkoxy groups having one or more oxygen linkages; aryloxy such as phenoxy; alkylthio groups; alkylsulfinyl groups; alkylsulfonyl groups; aminoalkyl groups such
  • substituents may include groups that include O, S, Se, N, P, Si, C and have between 2 and about 150 atoms. In some embodiments, it is useful to limit the size of any substituent to, e.g., less than about 150, less than about 100, less than about 50, or less than about 20 atoms.
  • Functional groups may also be substituted freely onto groups described herein; examples of such groups are described as FG in references to Formula 7.
  • the carrier material comprises a molecule having at least a portion that comprises a polypeptide backbone comprising homoamino acid sequences and/or heteroamino acid sequences, whereby the hydrophilic and hydrophobic balance is adjusted by chemical linkage to at least one side chain of the amino acids.
  • Hydrophobic groups may be added to increase hydrophobicity and hydrophilic groups may be added to increase hydrophilicity. Examples of hydrophobic groups are alkyls, alkenes, alkynes, aromatic groups (e.g., benzenes), many ringed structures (e.g., cyclohexane), and phospholipids.
  • hydrophilic groups are polyethylene oxides, sugar residues, polysaccharides, polyvinyl alcohols, polyethyleneimines, polyacrylic acids, and zwitterionic groups, e.g., a head group of a zwitterionic phospholipid.
  • the Tg of the polymer may be selected by addition of hydrophobic or hydrophilic groups; in such a case, a polymer is selected and hydrophobic or hydrophilic groups are added as needed to achieve a selected Tg.
  • the addition of hydrophobic or hydrophilic groups may be adjusted to achieve a selected rate of release of a selected therapeutic agent; in such a case, for example as shown in Figures 3-4 , the release rate of the agent from layers of polypeptides with varying derivitization of their side chains is measured.
  • the desired release profile is achieved by adjusting the number of derivatized side chains and the length of the hydrophobic or hydrophilic moieties on the side chains.
  • the domains formed by the relatively longer hydrophobic portions of the polyaminoacid may have been more conducive to migration of the agent through the material.
  • This acceleration of release is surprising and unexpected because relatively small changes in side chain length caused a disproportionate rate of increase in release. Further, this result is surprising because the rate of release would normally be expected to be highly related to the water solubility of the carrier material, with more soluble materials being more rapidly hydrated to accelerate release of agents therein. Accordingly, some embodiments are directed to polymers as described herein that have hydrophobic side chains of at least about 50-500 molecular weight.
  • the polypeptides which are also referred to herein as polyaminoacids, have a molecular weight between about 1,000 and about 4,000,000. Alternatively, the molecular weights may be between about 20,000 and about 250,000. The molecular weight has an influence on coatings made with these materials.
  • the side chains of a polypeptide may be partially derivatized or fully derivatized with respect to the total number of side chains, e.g., between about 1% and about 100%, or between about 3% and about 95% of the total number of side chains are derivatized. Persons of ordinary skill in these arts will immediately understand that all ranges and values within these explicitly stated molecular weight and derivitization ranges are contemplated.
  • polylysine may be modified by attaching a hexane to its side chains, e.g., with an N-hydroxysuccinimide ester as shown in Example 1.
  • the polylysine was soluble in aqueous solvents before modification, but, after being decorated with the hexanes, was insoluble in water.
  • the derivatized polylysine was soluble in alcohols and dimethyl sulfoxide (DMSO) and dimethylformamide (DMF). About 60% of the side chains of the polylysine were modified with the hydrophobic groups and subsequent processing was used to modify about 94% of all of the side chains.
  • Various polyamino acids with various molecular weights and monomer units may be derivatized, e.g., polylysine (Example 1), polyglutamate (Example 4), polyaspartate (Example 5), and polyaminoacids having other amino acids.
  • the degree of substitution can be controlled by altering the reactions, e.g., as in Example l(ii) and l(iii), so that substitution between about 1% and about 100% of the available side chains can be achieved.
  • the length of hydrophobic and hydrophilic groups can be varied, e.g., as in Examples 1-8, so that, e.g., side chains comprising polyethylene glycol or C 2 -C 50 may be achieved.
  • Copolymers having different amino acids may be synthesized, e.g., as in Example 7, wherein aspartate and glutamates were copolymerized and their side chains were derivatized. Further, derivatized portions of a polymer may be further derivatized to make them more hydrophobic or more hydrophilic.
  • Example 8 ethyl groups of derivatized polyaminoacid were converted to butyl groups using a transesterification process. And, for instance in Example 9, n-alkyl groups were transesterified to have glutamic acid side chains.
  • the extent of chemical modification influences the bioabsorbable rate and hence the rate of delivery of the therapeutic agent or diagnostic agent.
  • BIORELEASE shall refer to a polypeptide backbone comprising of homoamino acids and or heteroamino acids sequences, whereby by chemical linkage to the polypeptide backbone it is possible to adjust the hydrophilic and hydrophobic balance.
  • BIORELEASE-Lys30-Lauric50 shall refer to homo-polypeptide backbone comprising lysine sequences, 30 shall refer to molecular weight range of polylysine, the backbone is chemically modified to incorporate lauric acid and 50 shall refer to the degree of incorporation of laurate group, this can be achieved by reaction of the corresponding acid chloride or other suitable functional group with the amine on the polypeptide backbone.
  • drug loading into BIORELEASE is achieved by taking advantage the solubility of the drug and BIORELEASE in a suitable co-solvent such as iso-propylalcohol (IPA) / tetrahydrofuran (THF).
  • IPA iso-propylalcohol
  • THF tetrahydrofuran
  • BIORELEASE- Lys30-Lauric50 and paclitaxel which are found to be soluble in IPA / THF.
  • Medical devices such as stents, can be coated by dip-coating or spraying techniques. The release profile and the degradation rates may be measured in the laboratory.
  • BIORELEASE-Lysl.5-Lauric50 is made to chemically couple with BIORELEASE-Glul.5-Dodecan50 to give a final BIORELEASE composition of BIORELEASE (Lysl5-Lauric50)-(Glul5-Dodecan50).
  • BIORELEASE- Glul .5-Lauric50 is prepared by the reaction of the acid group on the polypeptide backbone with carbonyl diimadazole activated 1-dodecanol.
  • drug loading into BIORELEASE is achieved by taking advantage the solubility of the drug and BIORELEASE in a suitable co-solvent such as IPA / THF.
  • IPA / THF a suitable co-solvent
  • Medical devices, such as stents can be coated by dip-coating or spraying techniques. The release profile and the degradation rates may be measured in the laboratory.
  • individual amino acids are chemically modified by long chain hydrocarbons and these modified individual polypeptides are chemically linked to form BIORELEASE.
  • amino acid lysine is chemically modified with a long chain hydrocarbon such as stearoyl chloride to give (Lys-Stearic).
  • the amino acid glutamate is chemically modified with carbonyl diimadazole activated 1-dodecanol to give (Glu-Dodecan) and this is followed by chemical coupling to yield the BIORELEASE: [(Lys-Stearic) n -(Glu-Dodecan) m ]y (Formula 12), wherein n, m and y are the number of repeat units.
  • BIORELEASE-[(LS) justify-(GD) m ] y Hydrophobic and/or hydrophilic groups and/or therapeutic agents may be attached to an amino acid side chain in a variety of ways. For example, these may be attached via an amide, ester, carbonate, carbamate, oxime ester, acetal, ketal, urethane, ureas, enol ester, oxazolindies, anhydride, or oxime ester. As an example, a carbamate linkage may be used as follows:
  • Coatings are formed on an object.
  • other constructs e.g., sheaths, sleeves, membranes, and molded objects
  • coatings are distinct from other types of polymeric construct.
  • a sleeve, sheath, or membrane requires a certain minimum of mechanical robustness so as to maintain its identity before being associated with an object.
  • a process of coating creates an intimacy of contact between the coating and the device that is often desirable; for this reason, some processes involve coatings instead of other manufacturing procedures.
  • some processes of coating an object such as spraying or dipping create physical properties or processing opportunities that are not available in other processes.
  • a coating can have variable characteristics.
  • a coating may be discontinuous with a surface at some points and still retain its characteristic as a coating.
  • Coatings may also be formed of a single layer, or a plurality of layers. Coatings, and layers, can have a variable thickness, variable composition, variable chemical properties. Coatings, and layers, may cover all or a portion of a surface. Layers may, e.g., be superimposed upon other layers to create a coating.
  • Processes for forming a layer on an object may include applying a composition to a device by spraying, or by dipping the device into a composition for forming a polymeric layer.
  • a composition may be applied to a device by spraying, or by dipping the device into a composition for forming a polymeric layer.
  • Derivatized polypeptides taught herein may be formed in layers upon a medical device, including a layer that covers all of a device, a layer that covers a portion of the device, and layers upon other layers. Layers that contact each other may be crosslinked to each other, e.g., by covalent crosslinks between polymers in the layers.
  • Some embodiments of layers are formed by preparing a composition of derivatized polypeptides and applying them to a surface.
  • derivatized polypeptide may be applied to a device or layer and reacted there to form a layer.
  • Layers may also be crosslinked together.
  • One method is to apply a first layer that has a first set of reactive functional groups, and to apply a second layer that has a second set of reactive functional groups that form covalent crosslinks with the first set of functional groups.
  • the first layer and second layers may be applied in any order, e.g., starting with the first, then the second, or vice versa. Additional layers may be similarly formed and used.
  • Layers may be made from a single type of derivatized polypeptides, a plurality of derivatized polypeptide types, in combination with another compound, e.g., a polymer, or a combination thereof.
  • a single type of derivatized polypeptide could be used, or a plurality of derivatized polypeptide, each prepared separately, could be used.
  • a single reactive derivatized polypeptide could be mixed with reactable or unreactable polymers.
  • a layer may have reactive functional groups that are exposed to a chemical composition of polymers or non-polymers that have a functional group to react thereto. Or, for example, a layer may be exposed to reactive functional groups that are reactable thereto. For example, a layer may be exposed to a composition of light- activatable molecules that are triggered by light to react with the layer. Or a layer having nucleophilic groups may be exposed to a composition of molecules having electrophilic groups that react with the nucleophiles. Any of these layers may be associated with a therapeutic agent, and may be formed on a medical device with or without the presence of a therapeutic agent.
  • a therapeutic agent may be associated with the components of the layer, before, during, or after its application to a device.
  • a layer and a therapeutic agent may be essentially simultaneously applied to a device.
  • Such an application has some advantages, e.g., for ease of manufacturing.
  • a derivatized polypeptide may be associated with a therapeutic agent and the copolymer-therapeutic agent association may be applied to a device.
  • a therapeutic agent may be part of a composition that is applied to a surface that is subsequently activated to form new copolymers.
  • certain copolymers may advantageously be combined with a therapeutic agent to achieve delivery of the agent.
  • Therapeutic agents may be associated with a derivatized polypeptide before the derivatized polypeptide is applied to a device.
  • the derivatized polypeptide may be prepared and then exposed to a solution containing a solvent for the agent.
  • the agent and the derivatized polypeptide are allowed to interact, and the agent becomes associated with the derivatized polypeptide.
  • the therapeutic agent may be exposed to a derivatized polypeptide at essentially the same time that the agent and the copolymer are essentially simultaneously applied to a device.
  • the agent and the copolymer could be in the same or different solvent.
  • Nonsolvent and solvent are terms used somewhat broadly and include their strict meanings and also as including mixtures diluted with other substances.
  • Therapeutic agents also may be associated with a layer after the layer is applied to a device.
  • one suitable method comprises exposing the layer to a mixture comprising the agent.
  • the mixture may further comprise a relatively good solvent for both the agent and the layer so that the layer is swelled and the agent migrates therethrough. When the solvent is removed, the agent, or at least a portion thereof, remains in the layer.
  • Combinations of the above methodologies for associating the coating to the device can be used for the incorporation of a single therapeutic agent or a combination of therapeutic agents.
  • the application of a coating to a medical device may be adapted to the particular circumstances for that device.
  • the particular application may indicate what is suitable.
  • a stent for example, can be threaded through a tortuous system of blood vessel to reach its point of delivery in a patient. So a coating on the stent should have suitable physical properties and thickness.
  • the thickness of the polymeric layer is of a range that a therapeutic dose is delivered without impeding the effects of the drug and the performance of the medical device, for example a stent may have a polymeric layer in the range of, e.g., about 0.01 ⁇ m to about 150 ⁇ m, or between about 1 and about 300 ⁇ m.
  • ranges for other medical devices may vary widely, but some ranges are less than about 3 mm, less than about 1 mm, less than about 0.1 mm, less than about 0.01 mm, from about 1 to about 100 ⁇ m, from about 10 to about 1000 ⁇ m, from about 1 to about 10,000 ⁇ m, and from about 10 to about 500 ⁇ m; persons of ordinary skill in these arts will realize that all values and ranges within these explicit ranges are contemplated, and that other ranges may be suited as depending upon the device and/or application. Some devices and applications require an expandable or a flexible layer. As set forth in the Examples, embodiments herein can provide for flexibility and/or for expandability.
  • a stent With respect to a stent, most designs of stents require a step of expansion upon deployment in a patient. A layer that is expandable to accommodate the stent deployment is advantageous. With respect to a medical balloon, its use in the patient requires a step of expansion; accordingly, a coating on such a balloon may advantageously be made so as to accommodate that expansion.
  • An aspect of such coatings may be the hydrophobic balance of the coating. In the case of a hydrophobic therapeutic agent mixed into a hydrophobic coating, the diffusion of the agent though the coating may control a rate of release of the agent from the coating. The degree of hydrophobicity of the coating may be adjusted to affect the release rate.
  • the number of hydrophobic groups that are present correlates to the hydrophobicity of a coating made from a chemical described by one of the Formulas, with more hydrophobic groups causing an increase in hydrophobicity.
  • Medical devices Derivatized polypeptides may be made that are able to coat a given medical device, such as a stent; are able to incorporate therapeutic agents, e.g., diagnostic agents or other materials; and/or able to biodegrade into fragments that are biocompatible and non-toxic.
  • Medical devices include, for example any device that is implantable, used topically or otherwise comes in contact with living tissue at least for some period of time.
  • the devices could be made, for example, from polymers, such as catheters; from metals, such as guide-wires, stents, embolizing coils; from polymeric fabric, such as vascular grafts, stent grafts; from ceramics, such as mechanical heart valves, or a combination of these materials.
  • Other devices include, for example, heart valves, implantable cardiovascular defibriUators, pacemakers, surgical patches, patches, wound closure, micro-spheres, biosensors, sensors (implantable, ex-vivo and analyzers) ocular implants and contact lenses; medical devices that are made from ceramic, glass; tissue engineering scaffolds. At least partially degradable medical devices are also included. Examples of at least partially degradable medical devices include stents, e.g., urethral stent, abdominal aortic aneurysm stents, vascular stents, cardiac stents, coronary stents.
  • stents e.g., urethral stent, abdominal aortic aneurysm stents, vascular stents, cardiac stents, coronary stents.
  • At least partially biodegradable medical devices are embolizing coils, surgical patches, wound closures, ocular implants, dressings, grafts, and valves. Medical devices are also discussed in, e.g., U. S. Patent Application Nos. 5,464,650; 5,900,246; 6,214,901; 6,517,858; US 2002/0002353; and in patent applications WO 01/87342 A2; WO 03/024500, which are hereby incorporated herein by reference. Further embodiments include medical devices at least partially made of materials described herein, and which are at least partially degradable.
  • a medical device may be at least partially made of a copolymer that comprises a first monomer unit and a second monomer unit, with the first monomer unit comprising an amino acid and the second monomer unit comprising an amino acid derivatized to comprise a hydrophobic hydrocarbon side chain that has a molecular weight from about 14 to about 5000.
  • a medical device may be at least partially made of a polymer as set forth in Formulas 5-9.
  • the medical device may optionally include a therapeutic agent releasable into a patient after implantation of the device into the patient. Examples of medical devices and at least partially degradable medical devices are described, above.
  • Therapeutic agents Materials set forth herein may be associated with therapeutic agents, including, for example, drugs, imaging agents, diagnostic agents, prophylactic agents, hemostatic agents, tissue engineering agents, nitric oxide releasing agents, gene therapy agents, agents for enhancing wound healing, and bioactive agents.
  • a therapeutic agent may be mixed with a polymer precursor that is in solution or disposed in a solvent, and the polymer may be formed. Alternatively, the therapeutic agent may be introduced after the polymer is formed or at an intermediate point in the polymer formation process.
  • the term therapeutic agent is used to include, for example, therapeutic and/or diagnostic agents, and/or agents that are to be released from a coating. Many examples of therapeutic agents are set forth in priority document number 60/574,250. Therapeutic agents include, for example, those as disclosed in U. S.
  • Patent No. 6,214,901 additional embodiments of therapeutic agents, as well as polymeric coating methods, reactive monomers, solvents, and the like, are set forth in U. S. Patent Nos. 5,464,650, 5,782,908, 5,900,246, 5,980,972, 6,231,600, 6,251,136, 6,387,379, 6,503,556, and 6,517,858, each of which are hereby incorporated by reference herein.
  • Tg glass transition temperature
  • a polymer is a molecule composed of repeated subunits. Each subunit is referred to herein as a monomeric unit.
  • Polymers of only a few monomeric units are sometimes referred to as oHgomers.
  • the term polymer includes, for example, the meanings of homopolymer, copolymer, terpolymer, block copolymer, random copolymer, oligomer, and the like.
  • Some embodiments herein are directed to copolymers having certain Tg values or averages. Unless otherwise specified, the average Tg values are to be measured directly or estimated on the basis of weight of the monomer units.
  • An alternative method is to calculate an average by molar weight.
  • AVERAGE Tg ( lTgl + W2Tg2 + W3Tg3 + . . .
  • Tgl, Tg2, Tg3, and Tgn are the Tgs for the homopolymers of the first, second, third, and nth monomeric unit, respectively.
  • the Tg for a homopolymer varies with MW until about 20,000, so that a Tg for a homopolymer is customarily considered its Tg at or above about 20,000 MW. This procedure may be used to calculate the average Tg for a composition of monomeric units that are disposed in a copolymer.
  • a set of polymers therefore has an average weight and an average distribution of those weights. Therefore some embodiments relate to a set of polymers or polypeptides having a certain average or a distribution of properties or compositions and other aspects of polymers relate to calculating the average polymer weight.
  • One such method is the weight average molecular weight, which is calculated as follows: weigh a number of polymer molecules, add the squares of these weights, and then divide by the total weight of the molecules.
  • the number average molecular weight is another way of determining the molecular weight of a polymer. It is determined by measuring the molecular weight of n polymer molecules, summing the weights, and dividing by n.
  • the number average molecular weight of a polymer can be determined by, e.g., osmometry, end-group titration, and colligative properties, and various other methods exist for estimating the number average or weight average of polymers.
  • a polymer may include a block. A series of identical monomeric units joined together forms a block. A polymer may have no blocks, or a plurality of blocks. Blocks from a group of polymers or from one polymer may become associated with each other to form domains. Thermodynamic forces can drive the formation of the domains, with chemical attractions or repulsions between the blocks contributing to the driving force.
  • a copolymer is a polymer having at least two different monomeric units. Some copolymers have blocks, while others have random structures, and some copolymers have both blocks and regions of random copolymer bonding. Copolymers may be made from reactive monomers, oligomers, polymers, or other copolymers. Copolymer is a term that encompasses an oligomer made of at least two different monomeric units.
  • Tg Polymers, Tg, and Copolymers with monomeric units having a predetermined selected difference in Tg
  • Certain embodiments herein relate to copolymers formed from monomeric units that form homopolymers that have Tgs that have a selected difference between them.
  • Monomeric units are sometimes referred to herein as having a Tg, by which is meant the Tg of the homopolymer of about 20,000 molecular weight formed of the monomeric unit.
  • the predetermined differences set forth herein are believed to contribute to domain formation so that certain desirable polymeric properties are enhanced.
  • One such property is enhanced association of therapeutic agents with the domains.
  • the domain-domain interactions may create small microvoids for therapeutic agents, or may form chemical associations with the therapeutic agents, which can be bonding associations or electrostatic interactions.
  • Suitable predetermined Tg differences between monomeric units include at least about 30°C, at least about 50°C, and at least about 70°C. Other suitable differences in monomeric units Tgs are in the range of about 30°C to about 500°C, about 50°C to about 300°C, and about 70°C to about 200°C. Persons of ordinary skill in these arts, after reading this disclosure, will appreciate that all ranges and values within these explicitly stated ranges are contemplated.
  • Tg is an indirect and approximate indication of mobility of blocks or domains of a composition of copolymers. For copolymers having a non-covalent chemical or physical association with an agent, a greater mobility, or lower Tg, would be expected to result in a faster release of the agent.
  • a plurality of agents may be associated with a polymer, or a layer, or a coating, so that the Tgs are adjusted to reflect the chemistries of the agents.
  • Tg differences relate to the average Tg of the set.
  • polymeric implants loaded with a therapeutic agent can be made with polymers or copolymers having a Tg that is close to a physiological temperature.
  • the Tg of the monomeric units in a polymer provides an approximation of the Tg of the resultant polymer.
  • a weighted Tg average of a composition of monomeric units may be chosen for making a copolymer having desired properties.
  • Tg an average Tg that is suitable to achieve a change at a temperature for that application, e.g., movement form cryostorage to superheated steam, from CO 2 storage to oven, from freezer to boiling, from a cooler to a hot water bath, and so forth.
  • Weighted Tg averages for copolymers and polymers as set forth herein include from about -200°C to about 500°C, from about -80°C to about 250°C, from about -20°C to about 100°C, from about 0°C to about 40°C.
  • N-hydroxysuccinimide ester of hexanoic acid was synthesised using the procedure described in Y. Lapidot, S. Rappoport and Y. Wolman. Journal of Lipid Research, (1967) 142-145.3.
  • Hexanoic acid (20g, 0.172 moles) was added to a solution of N- hydroxysuccinimide (20g, 0.172 moles) in anhydrous ethyl acetate (750ml).
  • a solution of dicyclohexylcarbodiimide (35.49g, 0.172 moles) in anhydrous ethyl acetate (35ml) was added and the reaction mixture stirred at room temperature for 16 hours.
  • Dicyclohexylurea was removed by filtration, and the filtrate was concentrated under reduced pressure to yield a white precipitate.
  • the precipitate was washed with petroleum ether several times to remove dicyclohexylcarbodiimide, traces of hexanoic anhydride and hexanoic acid.
  • the product was dissolved in dithylether (100ml) and stored at 15°C for 16 hours. Traces of acylurea precipated and were removed byfiltration. Diethyether was removed under pressure to yield white crystals (20g, yield 50%). Thin layer chromatography (dichloromethane or petroleum ether (b.p. 40-60°C) - diethylether 8:2) gave a single spot.
  • N- hydroxysuccinimide ester of hexanoic acid (1.33g, 6.228 x 10 "3 moles) was dissolved in anhydrous DMSO (10ml) and was added dropwise. Then triethylamine (0.628g, 6.213 x 10 "3 moles) in a mixture of DMSO (8ml) and methanol (2ml) was added dropwise to the above and allowed to stir for 1 hour. The solution was poured into acetone (600ml) and allowed to stir for 10 mins.
  • the precipitate poly-L-lysine derivative was filtered and then re-suspended in acetone, stirred for 10 mins and filtered again and dried in a vacuum oven for 2 hours at 40°C. Yield was 2g of poly (L-lysine) graft n-hexyl copolymer.
  • the product was soluble in alcohols (methanol, ethanol and 2-propanol), DMSO, DMF but insoluble in water.
  • Gel permeation chromatography (GPC) gave a M.W. range of 80,000 - 160,000. The extent of coupling of hexanoic acid to poly L-lysine was found to be 60%.
  • the proportion of free amino groups in the grafted poly L-lysine may be measured by a comparative titration of the free amino groups in both the unmodified and modified poly L-lysine using TNBS.
  • the TNBS was carried out by dissolving the poly L-lysine graft n-hexyl copolymers (5mg) in methanol (10ml); 5mls of this solution was diluted to 10ml with sodium tetraborate (0.1M). TNBS solution (7.5 ul, 0.03M) was added to a 5ml aliquot of this methanolic sodium tetraborate solution.
  • Example 1 (ii) the percentage was 40%, hence a degree of incorporation of hexanoic acid of 60%.
  • Example 1 (iii) 6% was unmodified polymer and hence 94% incorporation of hexanoic acid onto poly L-lysine.
  • the hydrophobic/hydrophilic balance can be further achieved by grafting hydrophilic polyethylene glycol onto the poly L-lysine.
  • Example 1 (ii) using the partial coupling method, 85% of the free amino groups on poly L-lysine were coupled to hexanoic acid, as assayed using the TNBS procedure.
  • Polyethylene glycol monomethyl ether (FW 550) (lOg) was dissolved in anhydrous dichloromethane (50ml) and thereto was added dropwise carbonyldiimidazole (CDI) (2.95g) dissolved in 20ml dichloromethane.
  • CDI carbonyldiimidazole
  • Triethylamine (0.2ml; 1.44 x 10 "3 moles) was dissolved in methanol (5ml) and added dropwise thereto above. After addition the solution was allowed to stir for 4 hours. The product was precipitated into excess diether ether, filtered and re-suspended in diethyl ether and filtered and dried in vacuum (40°C) for 2 hours. The product was suspended in water (2L) and allowed to stir for 16 hours. The product was filtered and washed with water and dried in vacuum (40°C) for 6 hours.
  • Example 3 Graft poly (hexyl-L-lysine) with 94% incorporation of hexanoic acid (1.5g) (Example 2 (iii)) was dissolved in propan-2-ol (50ml). To a 10ml aliquot of the polymer solution was added the active agent paclitaxel (0.06g) dissolved in tetradydrofuran (THF) (10ml). A stainless steel coronary stent (18mm) was mounted onto a rotating mandrel and air sprayed with the above solution of propan-2-ol/THF containing polymer plus paclitaxel. The coated stent was vacuum dried at 70°C for 1 hour.
  • THF tetradydrofuran
  • Paclitaxel loading on the stent was measured by incubating a coated stent in acetonitrile (3ml), vortexing (30 seconds) and then measuring the absorbance at 227nm wavelength: drug loading was interpolated from a standard curve. Typical drug loading per stent was 100 ⁇ g+/-10%. Paclitaxel release profiles were performed in phosphate buffered saline (PBS) (0.5ml, pH 7.4) at 37°C. Readings were taken at intervals of 1 hour, 24 hours or 48 hours. Quantification of paclitaxel was performed on HPLC, using a Nucleosil TM 100-5CIS column (I.D.
  • Figs 1 & 2 show paclitaxel release profiles at 37°C from graft poly (hexyl-L- lysine) with 94%) incorporation of hexanoic acid.
  • Reaction Scheme 7 A 2 liter 3 -neck flask was equipped with stirrer, thermometer and additional funnel was charged with L-glutamic acid (22g, 0.15 moles), t-butyl alcohol (150ml) and n- tetradecanol (128.4g, 0.599 moles). This mixture was stirred and heated to 55°C and then sulphuric acid (97%) (12ml; 0.225 moles) was added dropwise thereto through the funnel.
  • the temperature of the mass was then raised to and maintained at 65°C until the mass became a clear solution.
  • the solution was maintained at 65°C for 1 hour.
  • the heat was turned off and triethylamine (10.4ml; 0.075 moles) was added dropwise thereto to neutralise free sulphuric acid. This was followed by the addition thereto of 40ml of water and then 550ml of 95% ethanol. Whilst stirring, triethylamine (20.9ml: 0.15 moles) was added thereto.
  • crude free glutamate precipitated and was filtered.
  • the recovered precipitate was slurried for 30mins at 65°C with water (500ml) and a solid cake was recovered.
  • the cake was washed with methanol (200ml) and then diethyl ether (200ml) and then dried at 50°C in a vacuum oven for 2 hours.
  • the crude precipitate was suspended in a mixture of water/2-propanol (2.5:1) and heated to 80°C and then cooled and filtered at 40°C.
  • the recovered precipitate was washed with cold water/2-propanol mixture, then with methanol (100ml) and finally diethyl ether (100ml) and dried in a vacuum oven at 30°C to constant weight.
  • the dry pure w-n-tetradecyl-L-glutamate weighed 15g (27% yield).
  • Example 5 Synthesis of Poly (gamma-n-tetradecyl-L-aspartate - (PTLA) PTLA was synthesised exactly as described in Example 4 for the synthesis of PTLG. Yield of intermediates and product were similar but the M.W. by GPC was 90,000-110,000.
  • PTLA gamma-n-tetradecyl-L-aspartate -
  • Octadecyl C18 were synthesised according to the procedure outlined in Example 4.
  • Example 8 Synthesis of Poly (gamma-n-butyl-L-glutamate - (PBLG) from Poly (gamma-n- ethyl-L-glutamate - (PELG) via transesterification.
  • PELG (lg) was dissolved in anhydrous l,2,dichloroethane with heating. The dissolved PELG gave a cloudy solution.
  • 1-Butanol (4g) was added thereto together with p-toluene sulphonic acid (0.3g). The mixture was refluxed at 80°C for 24 hours. At which point a clear solution resulted.
  • l,2,dichloroethane was evaporated under reduced pressure and then the product was suspended in methanol (50ml).
  • Example 9 An example of increasing the hydrophilic nature of poly-n-alkyl glutamates is to partially esterify n-alkyl groups onto polyglutamic acid.
  • Polyglutamic acid with sodium salt (M.W. 50,000-100,000) (lg) was dissolved in water (50ml) and thereto was added hydrochloric acid (0.1M) dropwise until the pH of the solution was 1.5. This was dialysed against water (10L) using Cellu Sep membrane M.W.C.O. 12,000-14,000 for 24 hours and freeze dried. Yield 0.7g.
  • the partial synthesis of poly-n-alkyl glutamate was performed as described in T. Shimokuri, T. Kaneko, T. Serizawa and M.
  • the product was filtered and dried in a vacuum oven (40°C) for 6 hours.
  • the esterification was confirmed by 'HNMR.
  • the degree of esterification as measured by J HNMR spectroscopy was 75%.
  • the polymer was insoluble in water but soluble in chloroform, benzene, DMF and DMSO.
  • someone skilled in the art may also produce partial esters of poly alkyl - L aspartate or a mixture of partial esters of poly alkyl-L-glutamate and poly alkyl-L-aspartate. This known procedure serves equally well for poly-n-alkyl-gamma-glutamate where one can have partial or total esterification depending on the molar ratio of the bromo alkyl used (T. Shimokuri, T. Kaneko, T. Serizawa and M. Akashi, Macromolecular Bioscience 4 (2004) 407-411).
  • Paclitaxel loading on the stents was measured by incubating a coated stent in acetonitrile (3ml), vortexing (30 seconds) and then measuring the absorbsance at 227nm wavelength. Drug loading was interpolated from a standard curve. Typical drug loading per stent was 120 ⁇ g +/-10%. Paclitaxel release profiles were performed in PBS (0.5ml, pH 7.4) at 37°C. Readings were taken at intervals of 1 hour, 24 hours or 48 hours. Quantification of paclitaxel was performed on HPLC, using a nucleosil TM100-5CIS column (I.D.
  • the films were dried and then circular films were cut to a defined diameter (50mm) using a cork -borer. The films were further dried to a constant weight (90-1 OOmg).
  • the circular films were incubated with lOml of solution in glass test tubes incubated at 37 °C.
  • the incubation solutions were: Phosphate buffer (200mM) pH 7.4 Phospate buffer plus 5mg of ⁇ -chymotrypsin. The above solutions were changed every 24 hours.
  • the films were removed from the incubating solution and washed with deionised water and dried to a constant weight. Table 1: Summary of the results obtained.
  • Example 12 In-vitro degradation of Poly-L-glutamate or aspartate derivatives was performed exactly as described in Example 11. The table below (Table 2) summarizes the results obtained.

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US20090176892A1 (en) * 2008-01-09 2009-07-09 Pharmain Corporation Soluble Hydrophobic Core Carrier Compositions for Delivery of Therapeutic Agents, Methods of Making and Using the Same
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EP2801379B1 (de) * 2012-03-27 2017-03-08 Terumo Kabushiki Kaisha Beschichtungszusammensetzung und medizinische vorrichtung
CN105797218B (zh) * 2012-03-27 2019-06-21 泰尔茂株式会社 涂布组合物及医疗器械
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USRE49528E1 (en) 2013-04-26 2023-05-16 Biointeractions Ltd. Bioactive coatings
CN105797220B (zh) * 2014-12-31 2020-07-31 先健科技(深圳)有限公司 可降解铁基合金支架
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US20030064965A1 (en) * 2001-10-02 2003-04-03 Jacob Richter Method of delivering drugs to a tissue using drug-coated medical devices
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